Scandium-mediated opening of aziridine carboxylates: A facile synthesis of aryl substituted tryptophans

Article abstract of DOI:10.1055/s-1998-1773

The treatment of enantiomerically pure L-serine-derived N-Cbz- or N-Fmoc-aziridine carboxylates with indole derivatives in the presence of a stoichiometric amount of Sc(OTf)3 in dichloromethane at 0°C or RT gives the aryl-substituted and protected tryptop

Full text of DOI:10.1055/s-1998-1773

754
LETTERS
SYNLETT
Scandium-Mediated Opening of Aziridine Carboxylates: A Facile Synthesis of Aryl
Substituted Tryptophans
Youssef L. Bennani,* Gui-Dong Zhu and Jennifer C. Freeman
Abbott Laboratories, Metabolic Diseases Research, D4MG, AP10; 100 Abbott Park Rd, Abbott Park, IL 60064-3500, USA
Received 12 December 1997
Abstract: The treatment of enantiomerically pure L-serine-derived N-
Cbz- or N-Fmoc-aziridine carboxylates with indole derivatives in the
as heating in chloroform at 78°C under screw-cap sealed-tube
conditions. Additionally, the reported yields vary between 3-46%, with
5
presence of a stoichiometric amount of Sc(OTf) in dichloromethane at
the majority in the low 30%, and in our hands, tended to be lower upon
prolonged heating. We intended to find a mild and high yielding
synthetic method which could eventually be used in solid phase
synthesis.
3
0°C or RT gives the aryl-substituted and protected tryptophan
derivatives in good yields. Attempts to catalyze the reaction are also
reported.
The ubiquitous and important nature of amino acids in biology,
biochemistry and chemistry, justifies the ever increasing research
interest. During the preparation of a series of short peptide and
Interest in lanthanide-mediated organic transformations has recently
gained momentum with applications ranging from aldol condensations,
6
1
7
to enantioselective Diels-Alder cycloadditions,
allylation of
8
9
10
11
peptidomimetic sequences, we needed to synthesize a variety of indole-
substituted tryptophans in order to alter tryptophan side-chain
interactions and to further increase the diversity element in our intended
aldehydes, Michael additions, glycosylations, and epoxide and
12
aziridine
opening. Recently, ytterbium triflate was successfully
employed to catalyze the alkylation of indoles by electron-deficient
2
13
chemical libraries. A survey of the literature for the preparation of such
olefins. We sought to explore the possibility of other Lewis acid-
3
4
systems revealed few methods, with one seemingly suited for our
mediated additions of substituted indoles to aziridinocarboxylates.
needs. In 1989, Sato and Kozikowski reported on the treatment of
protected aziridine carboxylates with indoles to give the corresponding
tryptophans. While this method is appealing, the reactions are sluggish,
Thus, we prepared benzyl (2S)-N-benzyloxy carbonyl-2-aziridine
14
carboxylate
2
from L-serine benzyl ester
and screened most
4
commercially available lanthanide triflates, including both yttrium and
scandium triflates as Lewis acids for this reaction. We wish to report
require the presence of typically 2-6 equivalents of zinc triflate, as well

July 1998
SYNLETT
755
herein that a variety of substituted indoles of type 1 add to aziridine 2, in
1.0 equiv.) and 1,2-dimethylindole (1.0 equiv.) were mixed in
the presence of Sc(OTf) in dichloromethane at 0°C or RT, to give the
dichloromethane at 0°C, followed by the addition of Sc(OTf) (1.0
3
3
corresponding substituted and protected tryptophans in good yields,
Scheme 1; Table 1.
equiv.) The mixture was stirred at 0°C under nitrogen for 3 h and
worked up as usual to give only 5% of 1,2-dimethylindole-derived
product as compared to 84% yield in entry 2, Table 1. This result is
indicative of a possible chelation of the amino acid ester to scandium.
A
representative procedure for the aziridine opening by 1,2-
dimethylindole (Entry 2) is as follows: To a solution of 1,2-dimethyl
indole (18.6 mg, 0.128 mmol) and benzyl N-CBz-2-aziridinecarboxylate
(20 mg, 0.064 mmol) in dichloromethane (1 mL), at 0°C was added
Sc(OTf) (32 mg, 0.064 mmol) under nitrogen atmosphere. The reaction
3
mixture was stirred at the same temperature for 3 hours. Water was
added, and the mixture was extracted with dichloromethane (3x10 mL).
The combined organic phases were washed with brine, dried over
Na SO , and concentrated under reduced pressure. The residual oil was
separated by flash chromatography (1:5 EtOAc/hexane) to afford
2
4
Figure 1
dimethyl N-CBz-L-Trp-OBn 3.2 (24.7 mg, 84%).
In summary, the above described method is simple, does not require
heating and allows for simple purification of the end products. We are
presently extending this method to other aziridines and to various
carbon and heteroatom nucleophilic systems both in solution and on
solid support.
Using indole as a nucleophile, reactions with most other lanthanide
triflates were messy or led to no product, with the exception of
3
Yb(OTf) , which induced a ~20% conversion of aziridine 2 to
3
tryptophan 3, along with other side products. The results depicted in the
15
Table clearly indicate that higher yields than previously reported by
other methods could be obtained in this reaction by using Sc(OTf) as a
3
Acknowledgment The authors are grateful to Mr. Michael Fitzgerald
Lewis acid at 0°C or RT. The enantiomeric purity of the reaction product
for optical purity analysis of the synthetic tryptophan by HPLC.
23
o
was examined by comparing the optical rotation of 3.1 ([α] –8.7 ,
c=1.7 in CH OH); with an authentic purchased sample of N-CBz-L-Trp-
3
References
23
o
4
OBn (Senn Chemicals AG; [α] –8.5 , (c=0.655 in CH OH). To
3
1.
a. Schultz, G. E.; Shriner, R. H. “Principles of Protein Structure”
Springer-Verlag, N.Y.; 1985;b. Williams, R. M.; “Synthesis of
Optically Active α-Amino Acids”, Pergamon Press, 1989.
further determine its optical purity, 3.1 was hydrogenated to tryptophan
using 10% Pd/C in ethanol. HPLC analysis of this amino acid using a
chiral column (Chiral Technologies Crownpak CR 4.6x150 mm, 10 mM
aq HClO ) revealed
enantiomeric purity could also be associated with the starting aziridine.
a 96% e.e. This minimal erosion of the
2.
For Combinatorial Chemical Library review articles see:
a. DeWitt, S.H.; Czarnik, A. W. Acc. Chem. Res. 1996, 29, 114;
b. Ellman, J. A. Acc. Chem. Res. 1996, 29, 132; c. Gordon, E.M.;
Gallop, M. A.; Patel, D. V. Acc. Chem. Res. 1996, 29, 144;
d. Rinnova, M.; Lebl, M. Collect. Czech. Chem. Comm. 1996,
171; e. Chem. Rev. 97, 1997, March-April entire issue.
4
Lower yields were obtained for those indoles with electron withdrawing
substituents. The reaction of aziridine carboxylate 2 with 5-nitro-2-
methylindole (entry 9) afforded only 22% of product after 30 hours at
25°C, while N-acetyl indole (entry 11) failed to give any product. Indole
(entry 1) and N-benzylindole (entry 7) gave lower yields as compared to
other substituted counterparts, presumably due to self condensation of
indole. Electron donating groups on indoles accelerated the reaction
(entries 2, 4, 5, 6 vs entry 1) while the presence of a hydroxy group
3.
a. Pfeil, E.; Harder, V. Angew. Chem. Int. Ed. Engl. 1967, 6, 178;
b. Styngach, E. P.; Kuchkova, K. I.; Efremova, T. M.; Semenov, A.
A. J. Heterocycl. Chem. 1973, 1378; c. Nakajima, K.; Okawa, K.
Bull. Chem. Soc. Jpn 1983, 56, 1565; d. Kogami, Y.; Okawa, K.
Bull. Chem. Soc. Jpn 1987, 60, 2963; e. Larsson, U.; Carlson, R.
Acta Chemica Scandinavica 1994, 48, 511; For the preparation of
completely suppressed the Sc(OTf) mediated opening of the aziridine.
3
β-amino ketones and esters by SmI -mediated opening of
aziridines, see: Molander, G. A.; Stengel, P. J. J. Org. Chem. 1995,
60, 6660.
Interestingly, bis-N,N’-dialkyl 2,2’-dimethylindole (entry 8) gave the
product resulting from addition of only one indole ring to the aziridine
in an isolated 51% yield, thus opening the possibility of differentiating
the two indole moieties.
2
4.
5.
Sato, K. Kozikowski, A. P. Tetrahedron Lett. 1989, 30, 4073
Under similar conditions, a 68% yield was obtained for the
reaction with 2-methylindole: Fukami, T., Yamakawa, T.;
Niiyama, K.; Kojima, H.; Amano, Y.; Kanda, F.; Osaki, S.;
Fukoroda, T.; Ihara, M.; Yano, M.; Ishikawa, K. J. Med. Chem.
1996, 39, 2313.
Elemental scandium, with a smaller radius than any other rare earth
element, has a chemical behavior known to be intermediate between that
16
of aluminum and other lanthanides. It is also known that various metal
triflates have been efficiently used to catalyze C-C bond forming
reactions such as Diels-Alder cycloadditions, and allylation of
6.
7.
Kobayashi, S.; Hachiya, I.; J. Org. Chem. 1994, 59, 3590 and
references cited therein.
17
aldehydes and imines. Yb(OTf) catalyzed aminolysis of aziridines
3
12
has also been reported. Attempts to catalyze the indole opening of
a. Kobayashi, S.; Ishitani, H.; Hachiya, I.; Araki, M. Tetrahedron
1994, 50, 11623; b. Markó, I. E.; Evans, G. R. Tetrahedron Lett.
1994, 35, 2771.
aziridine carboxylate 2 with up to 20% Sc(OTf) in the presence of a
3
variety of co-solvents and additives such as acids, tertiary amines, salts,
18
and other metals have not been fruitful yet. The possibility that the
8.
9.
Aspinall, H. C.; Browning, A. F.; Greeves, N.; Ravenscroft, P.
Tetrahedron Lett. 1994, 35, 4639.
produced amino acid ester is chelated to scandium, Figure 1, and thus
precluding
a catalytic cycle, was investigated by the following
Kobayashi, S. Synlett 1994, 689 and references cited therein.
experiment: N -benzyloxycarbonyl tryptophan benzyl ester (product
a
from entry 1) (2.0 equiv.), the starting aziridine carboxylate 2 (R =Cbz,
10. Kiessling, L. L.; Sanders, W. J. Tetrahedron Lett. 1994, 35, 7335.
5

756
LETTERS
SYNLETT
11. a. Chini, M.; Crotti, P.; Favero, L.; Macchia, F.; Pineshi,
Tetrahedron Lett. 1994, 35, 433; b. Meguro, M.; Asao, N.;
Yamamoto, Y. J. Chem. Soc. Perkin Trans. 1 1994, 2597.
14.0Hz, 1H); 3.76(s, 3H); 4.72(ddd, J=8.0, 6.0, 5.0Hz, 1H);
4.98(d, J=12.2Hz, 1H); 5.06-5.12(m, 3H); 5.33(d, J=8.1Hz, 1H);
6.76(dd, J=8.8, 2.5Hz, 1H); 6.94(d, J=2.2Hz, 1H); 7.10-7.13(m,
13
3H); 7.26-7.34(m, 8H); 7.64 (brs,1H)ppm. C NMR(75MHz,
12. Meguro, M.; Asao, N.; Yamamoto, Y. Tetrahedron Lett. 1994, 35,
CDCl ) δ 172.0, 155.8, 154.2, 136.2, 135.1, 133.8, 130.4, 128.5,
7395.
3
128.3, 128.1, 128.0, 111.0, 110.9, 105.4, 100.4, 67.2, 66.9, 55.9,
13. Harrington, Paul E.; Kerr, Michael A. Synlett 1996, 1047.
54.8, 27.6, 27.5, 11.6 ppm. MS(DCI/NH ) m/z: 473(20%, M+1).
3
14. Nakajima, K.; Takai, F.; Tanaka, T.; Okawa, K. Bull. Chem. Soc.
Jpn 1978, 51, 1978.
Anal. calcd for C
H N O : C, 71.17; H, 5.97; N, 5.93. Found:
28 28 2 5
C, 71.18; H, 6.01; N, 5.88.
3.8: IR(KBr) 3397(s), 1743(s), 1686(s) cm . H NMR (300MHz,
-1
1
15. Representative spectrometric data for the products of entries 2, 4,
6, and 8 of Table 1.
CDCl ) δ 1.22-1.38(m, 4H); 1.54-1.76(m, 4H); 2.19(s, 3H);
3
-1
1
3.2: IR(KBr) 3400(m), 1705(s) cm ; H NMR (300MHz, CDCl )
3
2.37(s, 3H); 3.23(dd, J=6.0, 14.1Hz, 1H); 3.30(dd, J=4.2, 15.0Hz,
1H); 3.94(t, J=7.7Hz, 2H); 4.00(t, J=7.4Hz, 2H); 4.69(ddd, J=8.2,
6.5, 5.0Hz, 1H); 4.92(d, J=12.1Hz, 1H); 5.05(d, J=12.1Hz, 1H);
5.07(d, J=12.2Hz, 1H); 5.10(d, J=12.2, 1H); 5.28(d, J=9.0Hz,
δ 2.21(s, 3H); 3.24(dd, J=6.3, 14.4Hz, 1H); 3.32(dd, J=4.8,
14.7Hz, 1H); 3.58(s, 3H); 4.71 (ddd, J=8.0, 6.0, 5.5Hz, 1H);
4.95(d, J=12.1Hz, 1H); 5.06-5.14(m, 3H); 5.30(d, J=8.9Hz, 1H);
7.03(t, J=8.0Hz, 1H); 7.10-7.37(m, 12H); 7.43(d, J=7.7Hz,
1H); 6.22(t, J=0.7Hz, 1H); 7.00-7.40(m, 16H); 7.42(d, J=7.7Hz,
13
1H)ppm. MS(DCI/NH ) m/z:457(100%, M+1). Anal. calcd for
3
1H); 7.51(d, J=7.3Hz,1H)ppm. C NMR(75MHz, CDCl ) δ
3
C
H N O : C, 73.66; H, 6.18; N, 6.14. Found: C, 73.85; H,
28 28 2 4
172.0, 136.2, 135.9, 134.8, 134.0, 130.6, 128.5, 128.3, 128.2,
128.1, 128.0, 127.3, 120.8, 120.4, 120.0, 119.3, 119.2, 117.9,
108.9, 108.8, 105.4, 99.9, 67.2, 66.8, 54.9, 43.2, 43.0, 30.1, 30.0,
6.26; N, 6.22.
3.4: IR(KBr) 3398,3350 (m), 1707 (s) cm . H NMR(300MHz,
-1
1
CDCl ) δ 2.24(s, 3H); 3.22(dd, J=6.3, 14.5Hz, 1H); 3.28(dd,
3
26.8, 12.8, 10.3 ppm. MS(DCI/NH ) m/z: 656(100%, M+1). Anal.
3
J=4.8, 14.5Hz, 1H); 4.72(ddd, J=8.1, 6.0, 5.0Hz, 1H); 4.97(d,
J=12.1Hz, 1H); 5.08(d, J=12.0Hz, 1H); 5.06(d, J=12.0Hz, 1H);
calcd for C
77.08; H, 7.06; N, 6.28.
H N O : C, 76.92; H, 6.92; N, 6.41. Found: C,
42 45 3 4
5.10(d, J=12.0Hz, 1H); 5.31(d, J=8.5Hz, 1H); 7.00-7.14(m, 4H);
16. Cotton, F. A.; Wilkinson, G. “Advanced Inorganic Chemistry” 5th
13
7.23-7.33(m, 9H); 7.42(d, J=7.7Hz,1H); 7.76(brs, 1H) ppm.
C
Ed., John Wiley & Sons: N.Y., 1988.
NMR(75MHz, CDCl ) δ 188.9, 171.9, 135.3, 135.1, 132.8, 128.5,
3
17. Bellucci, C.; Cozzi, G. P.; Umani-Ronchi, A. Tetrahedron Lett.
1995, 36, 7289.
128.3, 128.2, 128.1, 125.0, 121.3, 119.6, 117.9, 110.3, 105.8,
67.3, 66.9, 54.8, 27.5, 11.6ppm. MS(DCI/NH ) m/z: 443(100%,
3
+
M+1), 460 (80%, M+NH ). Anal. calcd for C
H N O : C,
18. Among the additives we tried: HMPA; triflic acid; triflic
4
27 26 2 4
73.29; H, 5.92; N, 6.33. Found: C, 73.08; H,6.08; N, 6.17.
3.6: IR(KBr) 3354 (m), 1713(s)cm . H NMR (300MHz, CDCl )
anhydride; acetic acid, Et N, Pyridine, LiBr, CeCl -(H O) ,
3 3 2 7
molecular sieves, Zn dust, ZnCl , Zn(OTf) , Ti(iPrO) and various
2 2 4
-1
1
3
δ 2.21(s, 3H); 3.19(dd, J=6.3, 13.8Hz, 1H); 3.25(dd, J=6.0,
others.